Prostate cancer (PCa) is the most common non-cutaneous malignancy in the United States males and is the second leading cause of cancer deaths in men. In this regard, epidemiologic data have also provided evidence of racial disparity, including younger age, higher incidence and aggressiveness of PCa at diagnosis and inferior survival rates of African Americans (AA) relative to Caucasian patients in the Unites States. The explanation for these differences is still unknown. On the other hand, our recent results combined with prior studies have revealed that MIC-1 and its functional partners EGFR and CXCR4 were more frequent in AA compared to Caucasian PCa patients. Importantly, recent reports have revealed that EGFR and CXCR4 mediate Docetaxel resistance in PCa cells. Therefore, the central hypothesis of this proposal is that the up- regulation of MIC-1 signaling cascade may cooperate with EGFR and CXCR4 oncogenic pathways for the acquisition of a more aggressive behavior, survival and therapeutic resistance of PCa cells and contribute to the racial disparity between AA versus Caucasian patients. The overall objective is to establish the signaling elements modulated by MIC-1/transforming growth factor- receptors (TGF-Rs) and their functional cross- talks with EGFR and CXCR4 cascades in tumor and tumor-associated stromal cells during prostate carcinogenesis and bone metastases that contribute to the ethnic disparity in AA vs. Caucasian patients. The therapeutic benefit to targeting MIC-1 cascade and its functional partners for reversing the chemoresistance of PC cells will also be investigated using PCa cell models and human PCa tissues from AA and Caucasian men. To test this hypothesis, three specific aims were proposed. Aim I will establish the involvement of MIC-1, EGFR and CXCR4 in racial disparity by performing immunohistochemical analyses of their expression on a large panel of benign and malignant tissues and DNA microarrays with PC cell lines relevant to AA and Caucasian men. Aim II will delineate molecular mechanisms of MIC-1 and its signaling cross-talks with EGFR and CXCR4 cascades involved in the growth, invasion and alterations of metabolic pathways using in vitro PCa cell models relevant to AA and Caucasian PCa patients. Aim III will determine the therapeutic benefit to target MIC-1 cascade for improving the anti-carcinogenic effects of docetaxel using in vitro and in vivo PCa cell models. Finally, we also demonstrate the molecular mechanism associated with Docetaxel resistance and its relationship with MIC-1 in PCa cells relevant to AA and Caucasian patients. Taken together, these studies will delineate the functional interplay between MIC-1 and its interacting partners EGFR and CXCR4 and their potential role in disease aggressiveness and therapy resistance to better understand their involvement in the racial disparity between AA and Caucasian patients. The overall outcome of this application will reveal the clinical interest to use combination of MIC-1, EGFR and CXCR4 as molecular biomarkers for an earlier and accurate diagnosis, response to therapy and impact on therapeutic intervention of AA and Caucasian patients.